The adipocyte-specific hormone, leptin, the product of the obese (ob) gene, acts on the hypothalamus to control appetite and energy expenditure (102). Leptin acts through the leptin receptor (leptin-R), a single transmembrane-domain receptor of the cytokine-receptor family (103). In 1997, Montague reported the first consanguineous family with two very obese prepubertal children who had congenital leptin deficiency (104). The two cousins were homozygous for a frameshift mutation in the leptin gene. Leptin administration to one of these children led to a sustained reduction of weight mainly because of suppressed food intake. Moreover, the patient's basal and stimulated gonadotropin levels increased after 1 yr of leptin therapy and a nocturnal LH secretion pattern was observed, characteristic of midpuberty (105). These findings might suggest a permissive role of leptin in the onset of puberty. In 1998, another consanguineous family with three affected obese individuals who had undetectable leptin levels was reported. Affected individuals were homozygous for a missense mutation (Arg105Try) in the leptin gene (106). Among the sibship, a 24-yr-old man failed to undergo puberty. He had low T and low gonadotropin levels, but a normal response to exogenous hCG and GnRH. Similar to the ob/ob mice with leptin mutation, these patients had morbid obesity, hyperinsulinemia, and hypogonadotropic hypogonadism, but unlike the mice, these patients were not hyperglycemic, had normal glucocorticoid concentrations, and did not present with growth abnormalities. In 1998, three sisters with obesity, hypogo-nadotropic hypogonadism, and elevated serum leptin levels have a leptin-R mutation (107). Genetic analysis revealed a homozygous mutation (G to A change) in the splice donor site of exon 16, resulting in skipping this exon during splicing. The resulted truncated receptor lacked the transmembrane and intracellular domains of the ob receptor. These results demonstrate the existence of hypothalamic hypogonadism in patients with leptin and leptin-R mutations and establish that leptin plays a key role in human reproduction (108).
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